It’s ironic that as more and more articles in the British Medical Journal, New
England Journal of Medicine, American Journal of Psychiatry (and the head of
NIMH, as well as the
Chair of the Task Force that published theDSM
IV), question both the underlying
science for the drugs and the drugs’ usefulness and efficacy, the forces
advocating forced treatment are pushing harder than ever to enact ever more
draconian laws.

The serotonin reuptake
inhibiting (SSRI) group of drugs came on stream in the late 1980s, nearly two
decades after first being mooted. The delay centred on finding an indication.
They did not have hoped for lucrative antihypertensive or antiobesity profiles.
A 1960s idea that serotonin concentrations might be lowered in depression1 had
been rejected,2 and
in clinical trials the SSRIs lost out to the older tricyclic antidepressants as
a treatment for severe depression (melancholia).345

When concerns emerged about
tranquilliser dependence in the early 1980s, an attempt was made to supplant
benzodiazepines with a serotonergic drug, buspirone, marketed as a
non-dependence producing anxiolytic. This flopped.6 The
lessons seemed to be that patients expected tranquillisers to have an immediate
effect and doctors expected them to produce dependence. It was not possible to
detoxify the tranquilliser brand.

Instead, drug companies marketed
SSRIs for depression, even though they were weaker than older tricyclic
antidepressants, and sold the idea that depression was the deeper illness behind
the superficial manifestations of anxiety. The approach was an astonishing
success, central to which was the notion that SSRIs restored serotonin levels to
normal, a notion that later transmuted into the idea that they remedied a
chemical imbalance. The tricyclics did not have a comparable narrative.

Serotonin myth

In the 1990s, no academic could
sell a message about lowered serotonin. There was no correlation between
serotonin reuptake inhibiting potency and antidepressant efficacy. No one knew
if SSRIs raised or lowered serotonin levels; they still don’t know. There was no
evidence that treatment corrected anything.7

The role of persuading people to
restore their serotonin levels to “normal” fell to the newly obligatory patient
representatives and patient groups. The lowered serotonin story took root in the
public domain rather than in psychopharmacology. This public serotonin was like
Freud’s notion of libido—vague, amorphous, and incapable of exploration—a piece
of biobabble.8 If
researchers used this language it was in the form of a symbol referring to some
physiological abnormality that most still presume will be found to underpin
melancholia—although not necessarily primary care “depression.”

The myth co-opted the
complementary health market. Materials from this source routinely encourage
people to eat foods or engage in activities that will enhance their serotonin
levels and in so doing they confirm the validity of using an antidepressant.9 The
myth co-opts psychologists and others, who for instance attempt to explain the
evolutionary importance of depression in terms of the function of the serotonin
system.10 Journals
and publishers take books and articles expounding such theories because of a
misconception that lowered serotonin levels in depression are an established
fact, and in so doing they sell antidepressants.

Above all the myth co-opted
doctors and patients. For doctors it provided an easy short hand for
communication with patients. For patients, the idea of correcting an abnormality
has a moral force that can be expected to overcome the scruples some might have
had about taking a tranquilliser, especially when packaged in the appealing form
that distress is not a weakness.

Costly distraction

Meanwhile
more effective and less costly treatments were marginalised. The success of the
SSRIs pushed older tricyclic antidepressants out of the market. This is a
problem because SSRIs have never been shown to work for the depressions
associated with a greatly increased risk of suicide (melancholia). The nervous
states that SSRIs do treat are not associated with increased risk of suicide.11The
focus on SSRIs also coincided with the abandonment of the pursuit of research
into established biological disturbances linked to melancholia (raised cortisol);
the SSRIs are ineffective in mood disorders with raised cortisol.12

Over two decades later, the
number of antidepressant prescriptions a year is slightly more than the number
of people in the Western world. Most (nine out of 10) prescriptions are for
patients who faced difficulties on stopping, equating to about a tenth of the
population.1314
These patients are often advised to continue treatment because their
difficulties indicate they need ongoing treatment, just as a person with
diabetes needs insulin.

Meanwhile studies suggesting
that ketamine, a drug acting on glutamate systems, is a more effective
antidepressant than SSRIs for melancholia cast doubt on the link between
serotonin and depression.151617

Serotonin is not irrelevant.
Just as with noradrenaline, dopamine, and other neurotransmitters, we can expect
it to vary among individuals and expect some correlation with temperament and
personality.18 There
were pointers to a dimensional role for serotonin from the 1970s onwards, with
research correlating lowered serotonin metabolite levels with impulsivity
leading to suicidality, aggression, and alcoholism.19As
with the eclipse of cortisol, this research strand also ran into the sand; SSRIs
lower serotonin metabolite levels in at least some people, and they are
particularly ineffective in patient groups characterised by impulsivity (those
with borderline personality traits).20

This history raises a question
about the weight doctors and others put on biological and epidemiological
plausibility. Does a plausible (but mythical) account of biology and treatment
let everyone put aside clinical trial data that show no evidence of lives saved
or restored function? Do clinical trial data marketed as evidence of
effectiveness make it easier to adopt a mythical account of biology? There are
no published studies on this topic.

These questions are important.
In other areas of life the products we use, from computers to microwaves,
improve year on year, but this is not the case for medicines, where this year’s
treatments may achieve blockbuster sales despite being less effective and less
safe than yesterday’s models. The emerging sciences of the brain offer enormous
scope to deploy any amount of neurobabble.21 We
need to understand the language we use. Until then, so long, and thanks for all
the serotonin.

Notes

Cite this as: BMJ
2015;350:h1771

Footnotes

·Competing
interests: I have read and understood BMJ policy on declaration of interests and
declare I am a founder member of RxISK, which works to raise the safety profile
of medicines and is on the advisory board of the Foundation for Excellence in
Mental Health Care. I have acted as an expert witness in cases relating to
suicide and violence and SSRIs.

Andrews PW, Bharwani A, Lee KR, Fox M, Thomson JA. Is serotonin an upper or a
downer? The evolution of the serotonergic system and its role in depression and
the antidepressant response.Neurosci
Biobehav Rev2015;51:164-88.
CrossRefMedline